Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase

Xingnan Zheng, Bo Zhai, Peppi Koivunen, Sandra J. Shin, Gang Lu, Jiayun Liu, Christoph Geisen, Abhishek A. Chakraborty, Javid J. Moslehi, David M. Smalley, Xin Wei, Xian Chen, Zhengming Chen, Justine M. Beres, Jing Zhang, Jen Lan Tsao, Mitchell C. Brenner, Yuqing Zhang, Cheng Fan, Ronald A. DePinhoJihye Paik, Steven P. Gygi, William G. Kaelin, Qing Zhang

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

The three EglN prolyl hydroxylases (EglN1, EglN2, and EglN3) regulate the stability of the HIF transcription factor. We recently showed that loss of EglN2, however, also leads to down-regulation of Cyclin D1 and decreased cell proliferation in a HIF-independent manner. Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. FOXO transcription factors can repress Cyclin D1 transcription. Failure to hydroxylate FOXO3a promotes its accumulation in cells, which in turn suppresses Cyclin D1 expression. These findings provide new insights into post-transcriptional control of FOXO3a and provide a new avenue for pharmacologically altering Cyclin D1 activity.

Original languageEnglish (US)
Pages (from-to)1429-1444
Number of pages16
JournalGenes and Development
Volume28
Issue number13
DOIs
StatePublished - Jul 1 2014
Externally publishedYes

Fingerprint

Cyclin D1
Hydroxylation
Transcription Factors
Prolyl Hydroxylases
Down-Regulation
Binding Sites
Cell Proliferation
Deubiquitinating Enzymes

Keywords

  • Breast cancer
  • Cyclin D1
  • EglN2
  • FOXO3a
  • Prolyl hydroxylation
  • USP9x

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. / Zheng, Xingnan; Zhai, Bo; Koivunen, Peppi; Shin, Sandra J.; Lu, Gang; Liu, Jiayun; Geisen, Christoph; Chakraborty, Abhishek A.; Moslehi, Javid J.; Smalley, David M.; Wei, Xin; Chen, Xian; Chen, Zhengming; Beres, Justine M.; Zhang, Jing; Tsao, Jen Lan; Brenner, Mitchell C.; Zhang, Yuqing; Fan, Cheng; DePinho, Ronald A.; Paik, Jihye; Gygi, Steven P.; Kaelin, William G.; Zhang, Qing.

In: Genes and Development, Vol. 28, No. 13, 01.07.2014, p. 1429-1444.

Research output: Contribution to journalArticle

Zheng, X, Zhai, B, Koivunen, P, Shin, SJ, Lu, G, Liu, J, Geisen, C, Chakraborty, AA, Moslehi, JJ, Smalley, DM, Wei, X, Chen, X, Chen, Z, Beres, JM, Zhang, J, Tsao, JL, Brenner, MC, Zhang, Y, Fan, C, DePinho, RA, Paik, J, Gygi, SP, Kaelin, WG & Zhang, Q 2014, 'Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase', Genes and Development, vol. 28, no. 13, pp. 1429-1444. https://doi.org/10.1101/gad.242131.114
Zheng, Xingnan ; Zhai, Bo ; Koivunen, Peppi ; Shin, Sandra J. ; Lu, Gang ; Liu, Jiayun ; Geisen, Christoph ; Chakraborty, Abhishek A. ; Moslehi, Javid J. ; Smalley, David M. ; Wei, Xin ; Chen, Xian ; Chen, Zhengming ; Beres, Justine M. ; Zhang, Jing ; Tsao, Jen Lan ; Brenner, Mitchell C. ; Zhang, Yuqing ; Fan, Cheng ; DePinho, Ronald A. ; Paik, Jihye ; Gygi, Steven P. ; Kaelin, William G. ; Zhang, Qing. / Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. In: Genes and Development. 2014 ; Vol. 28, No. 13. pp. 1429-1444.
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AU - Liu, Jiayun

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AU - Chakraborty, Abhishek A.

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AU - Beres, Justine M.

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AU - Brenner, Mitchell C.

AU - Zhang, Yuqing

AU - Fan, Cheng

AU - DePinho, Ronald A.

AU - Paik, Jihye

AU - Gygi, Steven P.

AU - Kaelin, William G.

AU - Zhang, Qing

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